Articles

Apoptogenic activity of auraptene of Zanthoxylum schinifolium toward human acute leukemia Jurkat T cells is associated with ER stress-mediated caspase-8 activation that stimulates mitochondria-dependent or -independent caspase cascade

Author

Jun D. Y, Kim J. S, Park H. S, Han C. R, Fang Z, Woo M. H, Rhee I. K, Kim Y. H.

Journal

Carcinogenesis

Volume

28

Issue ID

6

Page

1303-13

Date

2007 June.

Keyword

Alternative medicine
Apoptosis/drug effects*
Caspase 8/metabolism*
Caspase 8/physiology
Coumarins/pharmacology*
Endoplasmic Reticulum/drug effects
Endoplasmic Reticulum/enzymology*
Enzyme Activation/drug effects
Enzyme Activation/physiology
Humans
Jurkat Cells
Leukemia-Lymphoma, Adult T-Cell/drug therapy
Leukemia-Lymphoma, Adult T-Cell/enzymology*
Leukemia-Lymphoma, Adult T-Cell/pathology*
Mitochondria/drug effects
Mitochondria/enzymology*
Mitochondria/pathology
Phytotherapy
Signal Transduction/drug effects
Signal Transduction/physiology
Zanthoxylum*

Abstract

To isolate pharmacologically safe compounds that can induce apoptosis of tumor cells, leaves of an aromatic plant (Zanthoxylum schinifolium), which are widely used as a food flavor and herbal medicine in Korea and Japan, were sequentially extracted by organic solvents. An apoptogenic ingredient in the methylene chloride extract was further purified by silica gel column chromatography and identified as auraptene (AUR). The IC(50) value of AUR against Jurkat T cells was 16.5 microg/ml. After the treatment of Jurkat T cells with AUR, the endoplasmic reticulum (ER) stress-mediated activation of caspase-12 and -8 and subsequent apoptotic events including c-Jun N-terminal kinase (JNK) activation, cleavage of  FLICE inhibitory protein and Bid, mitochondrial cytochrome c release, activation  of caspase-9 and -3, degradation of poly (ADP-ribose) polymerase and apoptotic DNA fragmentation were induced in a dose-dependent manner. The cytotoxicity of AUR was not blocked by the anti-Fas neutralizing antibody ZB-4. The AUR-induced cytotoxicity and apoptotic events were abrogated by ectopic over-expression of Bcl-xL or addition of the pan-caspase inhibitor z-VAD-fmk. The individual or simultaneous addition of the m-calpain inhibitor (E64d), JNK inhibitor (SP600125) and mitochondrial permeability transition pore inhibitor (CsA) failed to prevent  apoptotic events including caspase-8 activation and Bid cleavage, unless the caspase-8 inhibitor (z-IETD-fmk) was combined, whereas AUR-induced caspase-12 activation was sustained even in the concomitant presence of z-IETD-fmk. These results demonstrated that the apoptotic effect of AUR on Jurkat T cells was exerted by the ER stress-mediated activation of caspase-8, and the subsequent induction of mitochondria-dependent or -independent activation of caspase cascade, which could be suppressed by Bcl-xL.

Language

English